title: Hepatic glycogen cycling contributes to glucose lowering effects of the glucokinase activator LCZ960.
abstract: Glucokinase (GK) acts as a glucose sensor by facilitating glucose phosphorylation into glucose-6-phosphate (G6P) in the liver and pancreas, the two key target tissues. LCZ960, a glucokinase activator exerts a stimulatory effect on GK activity in hepatocytes in vitro. This study aimed to verify in vivo that LCZ960 stimulates glucose uptake primarily through a mechanism involving hepatic GK activation. Acute and chronic LCZ960 treatment-induced changes in glycemia and hepatic glucose turnover were measured in high fat diet-induced obese (DIO) mice and rats. G6P production and glycogen cycling were quantified by (13)C-MR spectroscopy during a [1-(13)C]glucose infusion, followed by a pulse-chase with [(12)C]glucose to mimic postprandial conditions in rats. Acute treatment with LCZ960 dose-dependently reduced blood glucose without causing hypoglycemia in DIO mice. Chronic LCZ960 treatment maintained normoglycemia and improved glucose tolerance without increased insulin secretion in DIO mice and rats. In rats, LCZ960 stimulated a 240% increase (P<0.05) in the glycogen synthase flux. However, due to a much higher glycogen breakdown (LCZ960: 48 ± 15 vs control: 4 ± 1μmol/kg/min, P<0.05), this translated to only a 46% (ns) increase in glycogen storage (Vsyn net, LCZ960: 64±26 vs control: 43 ± 6 μmol/kg/min). Despite a 4-fold increase in hepatic glycogen turnover (LCZ960: 36.0 ± 5.5% vs control: 8.3 ± 2.0%), LCZ960 did not impact glucose-stimulated G6P accumulation. LCZ960 did not cause hypoglycemia in DIO rodents. Under hyperglycemic conditions, LCZ960 induced a robust increase in hepatic glycogen cycling. Since net hepatic glycogen storage is diminished in type 2 diabetes patients, stimulation of glycogen synthesis may contribute to the anti-hyperglycemic properties of glucokinase activation.
authors.affiliation: Department Novartis Institutes for BioMedical Research, Inc., Cambridge, MA 02139, USA. didier.laurent@novartis.com
authors.forename: Didier
authors.initials: D
authors.lastname: Laurent
authors.forename: Brittany
authors.initials: B
authors.lastname: Yerby
authors.forename: Bailin
authors.initials: B
authors.lastname: Zhang
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Gounarides
authors.forename: Jiel
authors.initials: J
authors.lastname: Zhang
authors.forename: Jiaping
authors.initials: J
authors.lastname: Gao
authors.forename: Gregory
authors.initials: G
authors.lastname: Bebernitz
authors.forename: Alokesh
authors.initials: A
authors.lastname: Duttaroy
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005941:Glucokinase / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C587697:3-cyclopentyl-2-(4-(4-methylpiperazine-1-sulfonyl)phenyl)-N-(5-pyridin-4-ylthiazolo(5,4-b)pyridin-2-yl)propionamide; D000577:Amides; D013449:Sulfonamides; D013844:Thiazoles; D019298:Glucose-6-Phosphate; D006003:Glycogen; D005941:Glucokinase; D005947:Glucose; C034666:propionamide
keywords: (13)C –MRS; Diabetes; Glucokinase activator; Glucose-6-phosphate; Glycogen